Annulation of Non-Conjugated Alkenes Via Directed Nucleopalladation

ARTICLE

https://doi.org/10.1038/s41467-020-20182-4 OPEN Anti-selective [3+2] (Hetero)annulation of non- conjugated alkenes via directed nucleopalladation

Hui-Qi Ni1, Ilia Kevlishvili2, Pranali G. Bedekar1, Joyann S. Barber3, Shouliang Yang3, Michelle Tran-Dubé3, ✉ ✉ ✉ Andrew M. Romine 1, Hou-Xiang Lu1, Indrawan J. McAlpine 3 , Peng Liu 2 & Keary M. Engle 1

2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures

1234567890():,; from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups. N-Acetyl, -tosyl, and -alkyl substituted ortho-iodoanilines,

as well as free –NH2 variants, are all effective. Preliminary results with carbon-based coupling partners also demonstrate the viability of forming indane core structures using this approach. Experimental and computational studies on reactions with phenols support a mechanism involving turnover-limiting, endergonic directed oxypalladation, followed by intramolecular oxidative addition and reductive elimination.

1 Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. 2 Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA. 3 Pﬁzer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, CA 92121, ✉ USA. email: indrawan.mcalpine@pﬁzer.com; [email protected]; [email protected]

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atalytic (hetero)annulation1–4 of C–C π-systems is a that the issues highlighted above could potentially be cir- Cpowerful method for constructing carbocyclic and het- cumvented by engaging an alternative mechanism, namely a erocyclic core structures from comparatively simple pro- sequence of Pd(II)-mediated Wacker-type nucleopalladation, genitor compounds. Of special importance within the modern followed by oxidative addition of the Ar–X bond to form a high- synthetic repertoire is the Pd(0)-catalyzed Larock indole synth- valent Pd(IV) intermediate, and finally C(sp3)–Ar reductive esis, first described in 19915, which unites alkynes and 2- elimination. If successfully developed, such a process would haloanilines (Fig. 1a). Later in 1995 and 2005, the Larock group potentially enable access to net anti-annulation, thereby com- reported analogous methods for benzo[b]furan and indene plementing existing methods, which proceed in a syn-selective synthesis6,7. Mechanistically, such reactions are generally believed fashion. Of relevance to this proposal, the Mazet and Zhang to proceed via oxidative addition, migratory insertion of the groups have described Pd(0)/Pd(II) heteroannulation systems in resultant arylpalladium(II) species, and C(sp2)–N/O/C reductive which syn-oxy/aminopalladation is proposed to take place from a • II 3 – elimination. Ln Pd (Ar)(X) intermediate, such that C(sp ) O/N bond for- While palladium-catalyzed alkyne annulation reactions are well mation precedes C(sp3)–Ar bond formation14–17. developed and widely deployed in preparative chemistry, During the past 5 years, our laboratories have developed a employment of alkenes in analogous processes is comparatively variety of transition-metal-catalyzed, three-component directed rare and limited to activated substrates like styrenes8–10, 1,3- alkene 1,2-difunctionalization reactions facilitated by the 8- dienes11, norbornenes12, and enol ethers/esters13–17 (Fig. 1b). aminoquinoline (AQ) auxiliary, a strongly coordinating biden- Extension of this mode of reactivity to unactivated alkenes has tate directing group. Using this strategy we and others have proven to be challenging for several interrelated reasons: (1) reported examples of hydrofunctionalization21–33, dicarbo- competitive β-hydride elimination following migratory insertion; functionalization34–39, carboamination40,41, and carbo-/amino- (2) inherently challenging C(sp3)–N/O/C reductive elimination18; boration42–45, among other transformations46,47 (Fig. 1c). We and (3) competitive alkene isomerization pathways19. In 2015, the recognized several issues that would need to be addressed to bring Jamison group reported an elegant method to access indolines a directed (hetero)annulation process to fruition: (1) phenols and from unactivated alkenes by taking advantage of nickel/photo- anilines have previously proven to be ineffective coupling part- redox dual catalysis20, though the reaction required use of an N- ners in AQ-directed alkene additions in our hands, leading to the acetyl protecting group and was only demonstrated with terminal hypothesis that nucleopalladation in these cases is endergonic; (2) alkenes, thereby limiting the product structures that can be due to their intramolecular nature, the oxidative addition and accessed. To our knowledge, analogous processes between O- reductive elimination transitions states involving Pd(IV) would based and C-based coupling partners and unactivated alkenes likely be highly strained; and (3) competitive pathways arising remain unknown. from Heck-type or Wacker-type oxidative alkene addition or In order to bridge this important synthetic gap, we sought to hydrofunctionalization could predominate. At the outset, our develop an all-encompassing annulation process that could unite hypothesis was that the presence of an ortho-halogen would allow non-conjugated alkenes and a diverse collection of O-based, N- for rapid trapping of a potentially short-lived nucleopalladated based, and C-based coupling partners. Specifically, we envisioned intermediate. In this work, by employing ambiphilic coupling partners we successfully achieve the (hetero)annulation of AQ-directed non- 48 a Larock-type [3+2] heteroannulation with alkynes conjugated alkenes , thereby providing direct access to useful R3 49–52 I cat. Pd0 2,3-dihydrobenzofurans, indolines, and indanes . Mechanistic + R2 R3 R2 experiments and DFT studies shed light on the origins of dia- NHR1 N R1 stereoinduction, anti-selectivity, and other aspects of this Pd(II)/ Pd(IV) annulation process. b Catalytic [3+2] heteroannulation with alkenes

Oxidative addition/ C–X Results syn-migratory insertion Reductive R2 cat. Pd0 elimination Scope of phenols. We began by using AQ-containing alkenyl I X 1 Mn R amide 1a as the model alkene and 2-iodophenol (2aa) as the or R2 X XH cat. NiI / R1 (syn) coupling partner. After brief optimization (see Supplemen- + IrIII + hv tary Information for details), we identiﬁed effective conditions Under 2 R2 developed R using Pd(OAc)2 (5 mol%) as the catalyst, K2CO3 (1.0 equiv) as 1 R PdIV the base, and HFIP (1.0 M) as the solvent, at 80 °C, under an air R1 cat. PdII X R2 X atmosphere, allowing for isolation of desired product 3aa in C–C 1 Anti-nucleopalladation/ R Reductive (anti) 96% yield. oxidative addition elimination Having identiﬁed a high-yielding and operationally simple c 1,2-Difunctionalization via directed nucleopalladation procedure, we next examined different ortho-iodophenols E O cat. PdII (Table 1). Phenols containing weakly electron-donating groups, Nu AQ t [Nu], [E] namely 4-Me (3ab) and 4- Bu (3ac), furnished the corresponding R (anti) O Nu = C or N products in 85% and 99% yield, respectively. 4-F (3ad), 4-Cl Previous work E = C, B, O, H N (3ae), 4-Br (3af), and 5-Br (3ai) phenols were also well tolerated H R N (AQ) II and gave moderate to high yields, demonstrating the reactions cat. Pd O I X compatibility with various halogen atoms. The presence of AQ strongly electron-withdrawing groups at the 4-position, namely R (anti) XH 4-CO2Me (3ag) and 4-(4-CN-C6H4)(3ah), led to lower yields. This work

Fig. 1 Background and project synopsis. a Larock-type [3 + 2] Scope of anilines. Next, we turned to evaluating the aniline scope + heteroannulation with alkynes. b Catalytic [3 2] heteroannulation with (Table 1). With free NH2 anilines, lowering the concentration to alkenes. c 1,2-difunctionalization via directed nucleopalladation. 0.5 M led to higher yields, and substrates with electron-

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Table 1 Scope of ortho-iodophenols, ortho-iodoanilines and carbon-based coupling partners.

R3 O I cat. Pd(OAc)2, K2CO3 + R3 O AQ XH HFIP, 80 °C, 24 h X AQ (X = O, NH, NR, [C]) 1a 2 3 Phenol Ar–I substitution b CN R X CO2Me Br I

O I O O O O O O O AQ O O AQ O O O AQ AQ AQ AQ O AQ 3aa, 96% [X-ray] 3ab, 85% (R = Me, ArI) 3ad, 89% (X = F) n.d. (R = Me, ArBr) 3ae, 75% (X = Cl) 3ag, 49% 3ah, 42% 3ai, 65% 3aj, 30% 3af, 84% (X = Br) 3ac, 99% (R = tBu) Aniline Ar–I substitution

CN F OMe MeO2C CO2Me MeO2C O O O O O O HN HN O AQ HN HN HN AQ HN HN AQ AQ AQ AQ AQ 3ba, 75% (ArI) 3bb, 99% 3bc, 73% 3bd, 47% 3be, 76% 3bf, 93% 3bg, 83% 53% (ArBr)

Me Me O Me I Br AQ O O O HN O NH2 HN + N HN AQ AQ AQ HN Br AQ AQ O 3bn, 32% 3bn’, 59%f [X-ray] 3bh, 66% (ArBr) 3bi, 47% 3bj, 50% d.r. = 1:1 Lmitations Aniline Het–I substitution Me Me R N N N N N I F N O O O O O HN HN HN NH2 AQ AQ HN AQ HN AQ AQ 2bk, n.r. (R=CO2Me) 2bl, n.r. (R=Me) a a a a 3bo, 85% 3bp, 63% 3bq, 56% 3br, 49% 3bs, 83% 2bm, n.r. (R=Br) Aniline N-substitution OMe

O O O O O O TsN AcN N MeN BnN AQ TsN AQ AQ AQ AQ AQ

3bt, >99% 3bu, >99% 3bv, 72%b 3bw, 90% (ArBr) 3bx, 50%c 3by, 58% c

Carbon-based coupling partners Limitations

I I O O O MeO2C EtO2C EtO2C CO2Me CN MeO2C AQ NC AQ PhO2S AQ

6b, 86%d,f 6c, 62% e,f e e 6a, 96%d 5d, n.r. 5e, n.r. d.r. = 1.5:1 d.r. = 1.3:1

Reaction conditions: 1a (0.1 mmol), 2 (1.2 equiv), Pd(OAc)2 (5 mol%), K2CO3 (1.0 equiv), HFIP (1.0 M for ortho -iodophenols and Ts-protected ortho -iodoanilines, 0.5 M for non-protected ortho-iodoanilines), air, 80°C, 24 h. Values correspond to isolated yields. a Pd(OAc)2 (20 mol%), HFIP (0.5 M), 100 °C. b KHCO3 (1.0 equiv), HFIP (2.0 M). c Pd(OAc) 2 (10 mol%), HFIP (2.0 M) d 1a (0.1 mmol), 5a–b (1.2 equiv), Pd(OAc)2 (10 mol%), K2CO3 (1.0 equiv), HFIP (2.0 M), air, 40°C, 24 h. e 1a (0.1 mmol), 5c (1.2 equiv), Pd(OAc)2 (10 mol%), K2CO3 (1.0 equiv), HFIP (2.0 M), air, 60°C, 24 h. f Values correspond to yields of a mixture of diastereomers. withdrawing groups performed better in this case. With ortho- (3bd) on the aromatic ring led to decreased yields. With electron- iodoaniline, 75% of the desired product 3ba was obtained, and donating groups, the product is prone to autooxidation to the pleasingly ortho-bromoaniline also provided product 3ba in 53% corresponding indole, particularly in the case of 3bd. 6-Me- yield. The ability to use bromoanilines is advantageous in many substituted 2-bromoaniline (3bh) was also compatible in this circumstances since they are easier to prepare and more readily reaction. 3-Substituted 2-iodoanilines were incompatible due to available from commercial suppliers than the corresponding the steric hinderance (2bk–2bm). iodoanilines. 4-, 5-, and 6-CO2Me-substituted 2-iodoanilines Given the importance of azaindole derivatives as building (3be–3bg) were all effective reaction partners, among which 5- blocks in medicinal chemistry53,54, we next tested aminoiodopyr- CO2Me (3bf) gave the highest yield of 93%. 4-CN-substituted 2- idines. Notably, compared to azaindoles, the synthesis of iodoaniline (3bb) delivered quantitative yield. Halogen atoms azaindolines has been less thoroughly studied. We were wary (3bc), alkyl groups (3bi, 3bj), and electron-donating substituents that the basic and coordinating azine nitrogen atoms could pose a

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Table 2 Alkene scope.

R3 I O cat. Pd(OAc)2, K2CO3 + R3 O AQ XH HFIP, 80 °C, 24 h X R1 R2 AQ (X = O, NH, NTs) 1b–1o 2aa , 2ba, or 2bt 4b-4o Alkenyl carboxylic acid derivatives

O O O O O O AQ TsN O O AQ AQ O AQ AQ O Me

OMe

(±)-4ba, 96% (±)-4ca, 86% (±)-4da, 90% (±)-4ea, 76% (±)-4cp, 85% [X-ray] d.r. = 12:1 d.r. > 20:1 d.r. > 20:1 d.r. > 20:1 d.r. > 20:1 (major diastereomer)

O O O O O O AQ O HN O HN AQ AQ AQ AQ Me Me Et Et

(±)-4ga from (Z)-alkene from (Z)-alkene from (Z)-alkene (±)-4fa, 46% [X-ray] from (Z): 93%, d.r. = 3:1 (±)-4gb, 74%a (±)-4ha, 47%b (±)-4hb, 54%c d.r. > 20:1 (major diastereomer) from (E): 86%, d.r. = 1.1:1 d.r. = 4:1 d.r. = 17:1 d.r. > 20:1

Alkenyl amine derivatives Limitations

(PA) O O O O O CO2Me Me O O N O AQ AQ H NHPA AQ AQ N Ph

4ja, 60% d Ph 4ia: 66% b d.r. = 1.6:1 4la, 16% (1H NMR yield) 1m, n.d. 1n, n.d. 1o, n.d. >99% ee (major) d.r. > 20:1 >99% ee (minor)

: Reaction conditions 1b–1o (0.1 mmol), 2aa, 2ba or 2bt (1.2 equiv), Pd(OAc)2 (5 mol%), K2CO3 (1.0 equiv), HFIP (1.0 M), air, 80°C, 24 h. Values correspond to yields of diastereomeric mixtures. a HFIP (0.5 M). b Pd(OAc) 2 (10 mol%). c Pd(OAc)2 (10 mol%), HFIP (0.5 M). d Pd(OAc) 2 (20 mol%), 40 °C, 24 h. significant challenge, as is often the case in Pd(II)-catalyzed Scope of carbon-based coupling partners. A small collection of reactions34,55. To our delight, however, various pyridine- carbon-based coupling partners were also compatible in this containing substrates were indeed compatible. For 3bo,we transformation, and the corresponding products 6a–6c could be – – obtained 85% yield under the standard conditions; for 3bp 3bs, obtained in 62 96% yield with 10 mol% Pd(OAc)2 and HFIP (2.0 higher Pd loadings and higher temperatures were employed, but M) (Table 1). Doubly activated pronucleophiles were required for these also gave satisfactory yields. Of note we were able to prepare efficient coupling (5d and 5e), and in the case of coupling part- 3br, which contains a fluorine atom at the sterically challenging ners bearing two different electron-withdrawing groups (6b and site ortho to the reactive iodide group. 6c), diastereoinduction was modest. This carboannulation Anilines containing a variety of N-substituents were then process56,57 enables preparation of indane structures that are tested, with different groups requiring different optimal reaction found in numerous natural products and pharmaceutical com- concentrations (see Supplementary Information). Tosyl (Ts) pounds58–60. proved to be a highly effective protecting group. The yield of the simplest Ts-protected 2-iodoaniline was >99% (3bt). In cases where the product is susceptible to autooxidation (e.g., OMe- Scope of alkenes. We moved on to explore the alkene scope containing compound 3bd), Ts protection leads to improved (Table 2). To our delight, reactions with α-substituted alkenyl yield (>99% yield, 3bu). Changing the protecting group to acetyl amides proceeded efficiently and with high diastereoselectivity. (Ac) (3bv) at higher concentration (2.0 M) gave a 72% yield. Even with a small moiety, in this case a Me group (4ba), we Tricyclic products (3bw) could also be formed in the reaction obtained 96% yield and 12:1 d.r. With a larger group at the α- conditions, and we were intrigued to observe 59% of the 1:1 position (4ca–4ea), >20:1 d.r. and 76–90% yield were obtained. cis/trans-configured diaddition product 3bn′ along with 32% An X-ray crystal structure of the Ts-protected products 4cp monoaddition product 3bn when using 2-bromo-6-iodoaniline. confirmed that the major product arises from C(sp3)–Ar bond Different N-alkyl 2-iodoanilines also proved to be effective in this formation on the face of the alkene opposite of the α-substituent reaction. By increasing the palladium loading and performing the (vide infra). A diene substrate (4fa) reacted exclusively at the β, γ- reaction at higher concentration, N-Me (3bx) and N-Bn (3by) alkene rather than the δ,ε-alkene, showcasing a unique example products were obtained in 50% and 58% yield, respectively. of chemoselectivity through substrate directivity. Notably, acyclic,

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a Pd(OAc)2 (5 mol%) b O I K2CO3 (1.0 equiv) O Ni(tmhd)2 (10 mol%) O + O X X AQ HFIP (0.5 M) HN NH2 N MeOH (0.1 M) OMe 23 °C, 18 h AQ H N 100 °C, 48 h, N2 [>10-gram-scale] 7aa (X = O), 81% 1aa, 50 mmol 2ba, 1.2 equiv 3ba, 14.3 g (94%) [simple purification] 3aa/3ba 7ba (X = NH), 89% c d O Pd(OAc)2 (5 mol%) O K CO (1.0 equiv) O O 2 3 O Y II AQ AQ Xn•Pd O AQ AQ I HFIP, 80°C, 24 h 8a (>95% recovered 8a) 3aa Reductive Ligand elimination/ exchange e Me ligand exchange O Me I Conditions A or B PhO + O O O AQ O 9a OH AQ N I N (ArOH) A: n.r. (>95% recovered 9a) II C–H 3ab IV N Pd B: 10% yield (1H NMR) Pd Y activation 2ab, 1.2 equiv N (CMD) X X

O O -O O oxy- elimination palladation -Y Oxidative via: N N O elimination I N addition II – N PdII N PdII – OPh– N Pd + ArO N L Nucleo- YH L X ArO N PdII palladation ArO X Y Conditions A: Pd(OAc)2 (5 mol%), K2CO3 (1.0 equiv), HFIP, 80°C, 24 h I Conditions B: Pd(OAc)2 (20 mol%) 1-Ad-CO 2H (0.5 equiv) MeCN, 120°C, 24 h

t g f Bu R tBu I

Pd(OAc) 2 (5 mol%) R I O OH K2CO3 (1.0 equiv) Pd(OAc)2 (5 mol%) O O K CO (1.0 equiv) O OH 2 3 2ac HFIP (1.0 M) AQ O AQ , 1.2 equiv 3ac 60 °C, 60 min + HFIP (1.0 M) O 2ac (R=tBu) t + + + AQ 60 °C 3ac (R= Bu) or AQ CO2Me or MeO2C I Initial rates 3ac:3ag = 3.8:1 1a 2aa (R=H) 3aa (R=H) 1a 29% combined or or OH v (3ac:3aa:3ag) = 4.7:4.6:1 1 O 2ag (R=CO Me) rel H NMR yield 2 3ag (R=CO2Me) O 1.2 equiv 2ag, 1.2 equiv AQ 3ag

Fig. 2 Large-scale reaction, directing group removal and mechanistic studies. a 50 mmol-scale reaction. b Directing group removal. c Proposed mechanism. d Viability evaluation of an alternative pathway. e Evaluation of the potential reversibility of C(sp3)–O bond formation. f Competition experiments. g Initial rate studies.

fi 61 non-conjugated internal alkenes, which are a dif cult substrate AQ amide alcoholysis method with catalytic Ni(tmhd)2 ,we class in nondirected systems due to issues with both reactivity and obtained 81% (7aa) and 89% yield (7ba) yields for representative selectivity, engaged in productive [3 + 2] heteroannulation. Both 2,3-dihydrobenzofuran and indoline products, respectively (Z)-alkenes and (E)-alkenes were compatible, with (Z)-alkenes (Fig. 2b). leading to higher d.r. (3:1 vs 1.1:1). According to previous studies of related transformations, internal alkenes are prone to E/Z 34–47 isomerization (see Supplementary Information), and (Z)-alkenes Mechanistic studies. In analogy to earlier work , we surmised react much faster in nucleopalladation than (E)-alkenes29,43. Both that the reaction may proceed by the general mechanism depicted ortho-iodophenol (4ga, 4ha) and ortho-iodoaniline (4gb, 4hb) in Fig. 2c, involving a sequence of alkene coordination, nucleo- worked well for internal alkenes, and the X-ray crystal structure palladation, intramolecular oxidative addition, and reductive of 4ga shows that the major product is in the trans configuration. elimination. To evaluate the viability of an alternative pathway Moreover, alkenyl amine substrates containing a 2-picolinyl comprised of alkene hydrofunctionalization followed by intra- 3 – 62,63 fi amide (NHPA) directing group were also competent substrates. molecular C(sp ) H arylation ,we rst performed a control For the simple alkene and simple ortho-iodophenol (4ia), we experiment in which compound 8a was subjected to the standard reaction conditions (Fig. 2d). In this case, no product isolated 66% yield by using 20 mol% Pd(OAc)2. Using an opti- cally pure allylglycine starting material, we obtained 60% yield was formed (with quantitative starting material recovery), (4ja), 1:1.6 d.r. and >99% e.e without any enantiomerization by establishing that 8a is not a competent intermediate. This result is 3 – reducing the reaction temperature to 40 °C. inconsistent with the two-step hydrofunctionalization/C(sp ) H arylation mechanism. Next, to evaluate the potential reversibility of the C(sp3)–O bond formation step, we used compound 9a as a Large-scale reaction and directing group removal. This meth- starting material (Fig. 2e). Under the standard conditions, no odology could be conveniently scaled-up (Fig. 2a) and allowed for reaction was observed. However, in the presence of 1-Ad-CO2H, isolation of 14.3 g of 3ba with minimal impurities after an which presumably facilitates C(sp3)–H activation via a concerted operationally simple work-up and purification procedure metalation/deprotonation (CMD) mechanism64, we were able to (see Supplementary Information). Using the Morimoto–Ohshima observe small amounts of the [3 + 2] product 3ab. The result

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a O O ΔG N (kcal/mol) N 35.9 N Pd N Pd 33.9 H TS4 O O O I TS2 O I Me TS4 TS2 O O O N N N OAc− N Pd N Pd N Pd 18.0 17.4 I I OAc TS1 O 15.9 O O HOAc TS3 TS1 I − TS5 OAc OH 10.4 I 9.9 HOAc 12 8.2 13 2aa 14 2aa + O O O − 2.8 OAc N N N 0.0 11 HOAc N Pd N Pd N Pd 2aa O 10 OAc I I O I O O −16.0 O N O O N Pd 14 15 N N O N Pd 12 13 N Pd I 15 10 OAc 11 I b O O O O O Me Me Me Me O TS6 N TS8 N N TS9 N TS7 Me 19.0 17.7 N Me 17.4 N Pd 17.8 N Pd O O N Pd N Pd N N Pd I O O I N Pd Anti- Oxidative I O Oxidative I Anti- H O AQ AQ OAc H nucleo- O addition addition O nucleo- Me OAc palladation (favored) Me (disfavored) palladation 17 0.2 (±)-4ba 21 16 18 20 experimental 19 12.2 0.0 10.5 8.8 d.r. = 12:1 11.4 N All energies are ΔG in kcal/mol with respect to 16. = N N N

Fig. 3 Computational studies. a Computed energy proﬁles of the Pd-catalyzed [3 + 2] heteroannulation of 1a and 2aa. Calculations were performed using Gaussian 16 at the M06/SDD-6-311++G(d,p)/SMD(HFIP)//B3LYP-D3/SDD-6-31G(d) level of theory. b DFT calculations on the origin of diastereoselectivity with alkene 1b. suggests that C(sp3)–O bond formation is reversible from the inner-sphere syn-addition pathway (TS2) from phenolate complex alkylpalladium(II) species—at least when accessed through this 11 is disfavored and requires a barrier of 33.9 kcal/mol. The pal- alternative C(sp3)–H activation pathway. An analogous experi- ladacycle intermediate 12 is 10.4 kcal/mol less stable than 10. The ment with 8a furnished an approximate 1:1 mixture of 3aa and endergonicity is consistent with control experiments that indicate 3ab in <10% combined yield (see Supplementary Information), reversible nucleopalladation when this intermediate is accessed consistent with the notion that C(sp3)–O bond formation is through an independent route (Fig. 2d). Dissociation of the acetate reversible and that oxidative addition and β-O elimination have anion from 12 and the coordination of the ortho-iodo group to Pd similar energy barriers from the putative alkylpalladium(II) forms complex 13, which promotes the intramolecular oxidative intermediate. addition (OA) (TS3, ΔG‡ = 17.4 kcal/mol). The resulting Pd(IV) Next, a series of competition experiments were conducted. A complex 14 can undergo a relatively facile reductive elimination one-pot experiment with electron-poor 2ag and electron-rich 2ac (TS5) with a barrier of 7.7 kcal/mol with respect to 14. The revealed the product-determining step is accelerated by electron- competing protodepalladation of palladacycle 12 with acetic acid donating groups (Fig. 2f). This trend was recapitulated when (TS4) is kinetically inaccessible, requiring an activation energy of global rates in single-component experiments were measured 35.9 kcal/mol. In the overall annulation reaction from complex 10, (Fig. 2g), which is consistent with either oxypalladation or C the nucleopalladation is the turnover-limiting step. Although the (sp3)–Ar reductive elimination (with the Ar fragment acting as formation of palladacycle 12 is endergonic, the intramolecular the nucleophilic moiety40) as the turnover-limiting and product- oxidative addition/reductive elimination is entropically facilitated determining steps for phenol substrates. and proceeds without signiﬁcant distortions in either transition state. It is notable that in this model reaction between 1a and 2aa, Computational studies. To clarify the reaction mechanism, nucleopalladation and oxidative addition are computed to have density functional theory (DFT) calculations were performed very similar barriers (TS1 vs. TS3). This raises the possibility that (Supplementary Data 1) on the reaction of alkene 1a and iodo- in reactions with other alkene substrates and coupling partners, phenol 2aa (Fig. 3a). The reaction starts with the complexation of the rate and selectivity could be controlled by either of these two the Pd(II) catalyst with 1a to form π-alkene complex 10. Several steps (vide infra). syn-nucleopalladation and anti-nucleopalladation pathways were Last, we investigated the origin of diastereoselectivity in evaluated computationally. The most favorable pathway proceeds reactions with α-substituted alkenyl amides. We modeled the through the anti-addition of deprotonated phenolate anion to 10 reaction of alkene 1b bearing a small α-methyl substituent and (via TS1), requiring a barrier of 18.0 kcal/mol. The competing iodophenol 2aa (Fig. 3b). The two diastereomeric products are

6 NATURE COMMUNICATIONS | (2020) 11:6432 | https://doi.org/10.1038/s41467-020-20182-4 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20182-4 ARTICLE formed via nucleopalladation of two nearly isoenergetic com- 7. Zhang, D., Yum, E. K., Liu, Z. & Larock, R. C. Synthesis of indenes by the plexes 16 and 17 with two opposite π-faces of the alkene bound to palladium-catalyzed carboannulation of internal alkynes. Org. Lett. 7, – the Pd. The nucleopalladation of 16 (TS6, ΔG‡ = 17.4 kcal/mol) 4963 4966 (2005). Δ ‡ = 8. Emrich, D. E. & Larock, R. C. Palladium-catalyzed heteroannulation of cyclic is only slightly more favorable than that of 17 (TS7, G 17.7 alkenes by functionally substituted aryl iodides. J. Organomet. Chem. 689, kcal/mol), due to the relatively early transition states. The 3756–3766 (2004). diastereoselectivity is determined in the subsequent oxidative 9. Buarque, C. D. et al. 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Balaich, Dr. Milan Gembicky, Maximilian G. Bernbeck, and Dr. Jake B. Bailey via directed aminopalladation. J. Am. Chem. Soc. 139, 11261–11270 (2017). (USCD) are acknowledged for assistance with X-Ray crystallography. We thank Prof. 41. van der Puyl, V. A., Derosa, J. & Engle, K. M. Directed, nickel-catalyzed Zachary K. Wickens and his group at UW Madison for helpful discussion. This work was umpolung 1,2-carboamination of alkenyl carbonyl compounds. ACS Catal. 9, financially supported by the National Institutes of Health (5R35GM125052-03; 224–229 (2019). 1R35GM128779), Pfizer, Inc., the Alfred P. Sloan Fellowship Program, the Camille 42. Liu, Z., Ni, H.-Q., Zeng, T. & Engle, K. M. Catalytic carbo- and aminoboration Dreyfus Teacher-Scholar Program, and the Cottrell Scholars Program. Calculations were of alkenyl carbonyl compounds via five- and six-membered palladacycles. J. performed at the Center for Research Computing at the University of Pittsburgh and the Am. Chem. 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